Benzenesulfonic Acid → N,alpha-bis(4-fluorophenyl)-4-piperidinemethanamine

HRID 1614638Notes

Reaction equation

HRID 1614638 reaction equation
Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=O)=[CH:5][CH:4]=1.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C1(S(O)(=O)=O)C=CC=CC=1.[BH4-].[Na+].[OH-].[Na+]>O.C(O)C>[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][CH:7]([C:6]2[CH:15]=[CH:16][C:3]([F:2])=[CH:4][CH:5]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:20][CH:19]=1

Participants

8

Reactant 5

HCID 7371Benzenesulfonic AcidHCID 97314-FluoroanilineHCID 14798Sodium HydroxideHCID 3084438p-Fluorophenyl 4-piperidyl ketone hydrochlorideHCID 4311764Sodium borohydride

Product 1

HCID 19771957N,alpha-bis(4-fluorophenyl)-4-piperidinemethanamine

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent2×

Conditions

Temperature
50 °C

Procedure

A stirred mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (40.0 g, 0.164 mole), 4-fluoroaniline (22.0 g, 0.197 mole), and benzenesulfonic acid (0.14 g) in xylenes (820 mL) was heated at reflux temperature for 18 hr during which time 3 mL of water was collected in a Dean-Stark trap. After cooling to 50° C., sodium borohydride (12.5 g, 0.328 mole) was added slowly. Ethanol (100 mL) was added and the mixture heated at 60° C. for 1 h. After stirring for 18 h under a nitrogen atmosphere at room temperature, the mixture was chilled to 5° C. with an ice bath and chilled water added cautiously. A rapid evolution of gas occurred causing a portion of the reaction mixture to spill over into the ice bath. The contents of the ice bath and the remainder of the reaction mixture were combined and basified with 50% sodium hydroxide solution, causing a viscous insoluble oil to separate from the mixture. The material was dissolved in ethyl acetate. The ethyl acetate solution and the xylene layer were combined and washed with additional dilute aqueous NaOH solution. The aqueous layers were combined and extracted with ethyl acetate-acetonitrile (60:40). The organic layers were combined and extracted twice with 300 mL portions of 3N HCl solution. The acid extract was basified with 50% sodium hydroxide solution and extracted twice with 600 mL portions of ethyl acetate-acetonitrile (60:40). The extracts were combined, treated with charcoal, dried (MgSO4), and concentrated. The residual material was heated at 100° C. under vacuum for 1 h to remove excess 4-fluoroaniline. The yield was 24.8 g (50.5%).

Workup

  1. temperaturewas heated
  2. customwas collected in a Dean-Stark trap
  3. temperaturethe mixture heated at 60° C. for 1 h
  4. temperaturethe mixture was chilled to 5° C. with an ice bath
  5. additionadded cautiously
  6. customto separate from the mixture
  7. dissolutionThe material was dissolved in ethyl acetate
  8. washwashed with additional dilute aqueous NaOH solution
  9. extractionextracted with ethyl acetate-acetonitrile (60:40)
  10. extractionextracted twice with 300 mL portions of 3N HCl solution
  11. extractionThe acid extract
  12. extractionextracted twice with 600 mL portions of ethyl acetate-acetonitrile (60:40)
  13. additiontreated with charcoal
  14. dry with materialdried (MgSO4)
  15. concentrationconcentrated
  16. temperatureThe residual material was heated at 100° C. under vacuum for 1 h
  17. customto remove excess 4-fluoroaniline

Sources & evidence

ORD record
ord-cb2d27bd0f634605b591e304bc584e2b
Source dataset
uspto-grants-1993_03
Patent number
US05198449

Reaction notes

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